title: Correlation of hydrogen-bonding propensity and anticancer profile of tetrazole-tethered combretastatin analogues.
abstract: A series of 1,5-disubstituted tetrazole-tethered combretastatin analogues with extended hydrogen-bond donors at the ortho-positions of the aryl A and B rings were developed and evaluated for their antitubulin and antiproliferative activity. We wanted to test whether intramolecular hydrogen-bonding used as a conformational locking element in these analogues would improve their activity. The correlation of crystal structures with the antitubulin and antiproliferative profiles of the modified analogues suggested that hydrogen-bond-mediated conformational control of the A ring is deleterious to the bioactivity. In contrast, although there was no clear evidence that intramolecular hydrogen bonding to the B ring enhanced activity, we found that increased substitution on the B ring had a positive effect on antitubulin and antiproliferative activity. Among the various analogues synthesized, compounds 5d and 5e, having hydrogen-bonding donor groups at the ortho and meta-positions on the 4-methoxy phenyl B ring, are strong inhibitors of tubulin polymerization and antiproliferative agents having IC50 value in micromolar concentrations.
authors.affiliation: Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India.
authors.forename: Ganesh S
authors.initials: GS
authors.lastname: Jedhe
authors.forename: Debasish
authors.initials: D
authors.lastname: Paul
authors.forename: Rajesh G
authors.initials: RG
authors.lastname: Gonnade
authors.forename: Manas K
authors.initials: MK
authors.lastname: Santra
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Tam Luong
authors.initials: TL
authors.lastname: Nguyen
authors.forename: Gangadhar J
authors.initials: GJ
authors.lastname: Sanjayan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D013777:Tetrazoles; D050257:Tubulin Modulators; C040105:combretastatin
keywords: Colchicine; Combretastatin; Crystal; Tetrazole; Tubulin